Abstract

Cancer metastasis accounts for the high mortality of many types of cancer. Owing to the unique advantages of high specificity and minimal invasiveness, photothermal therapy (PTT) has been evidenced with great potential in treating cancer metastasis. In this review, we outline the current approaches of PTT with respect to its application in treating metastatic cancer. PTT can be used alone, guided with multimodal imaging, or combined with the current available therapies for effective treatment of cancer metastasis. Numerous types of photothermal nanotherapeutics (PTN) have been developed with encouraging therapeutic efficacy on metastatic cancer in many preclinical animal experiments. We summarize the design and performance of various PTN in PTT alone and their combinational therapy. We also point out the lacking area and the most promising approaches in this challenging field. In conclusion, PTT or their combinational therapy can provide an essential promising therapeutic modality against cancer metastasis.

1. Introduction

Cancer metastasis is one of the greatest challenges in cancer therapy, which is responsive for over 90% of cancer-related deaths of many types of cancers [1-3]. The metastasis is a complex multistep process and displays a remarkable diversity in clinical features, which refers to the dissemination of cancer cells from primary tumor to colonization at distant secondary sites [1, 2, 4]. Once the metastasis occurs at distant organs, it becomes largely incurable and fatal. To date, current available therapies including aggressive surgery, radiotherapy and chemotherapy, have been utilized for treating cancer metastasis, but only have limited curative effects in patients with metastatic cancers [1, 5-8]. Despite the recent progress in new therapeutic agents, targeted therapies and combinational regimens, the therapeutic efficacy of cancer metastasis is still very pessimistic, with an improvement in overall survival of only a few months at most [2, 9-11]. Typically, for metastatic breast cancer patients experiencing intense multimodal treatments, the five-year survival rate is only about 20% [12, 13].

Photothermal therapy (PTT) is a newly developed and encouraging therapeutic strategy, which employs the near-infrared (NIR) laser photoabsorbers to generate heat for thermal ablation of cancer cells upon NIR laser irradiation [14-16]. Compared with the conventional therapeutic modalities, PTT exhibits unique advantages in cancer therapy including high specificity, minimal invasiveness and precise spatial-temporal selectivity, etc [14, 15, 17, 18]. PTT can directly eradicate the cancer cells in primary tumor or local metastasis in lymph node nearby to combat the initial stage of cancer metastasis, and also be combined with current therapeutic modalities to treat cancer cells in the metastatic sites [19-22]. Recently, the potential application of PTT in treating cancer metastasis has been explored in many groups including ours [19, 22-24]. The therapeutic efficacy of PTT significantly depends on the transformation of light to sufficient heat with photothermal agents, especially nanoscale agents. To date, a variety of photothermal nanotherapeutics (PTN) including noble metal nanostructures, nanocarbons, transition metal sulfide/oxides nanomaterials, and organic nanoagents have been extensively explored[14, 25]. PTT can be used alone, guided by multimodal imaging, or combined with the current available therapies to realize their therapeutic outcome [26-29]. So far, PTT or their combinational therapy has been investigated in animal models with lung, bone or lymph metastasis of many types of cancer, and presents promising therapeutic efficiency.

The rationale of this review is to outline the current approaches of PTN with respect to its use in treating cancer metastasis. We mainly summarize the components, structure and design of various PTN and their therapeutic effect in PTT alone or their combinational therapy with current management modalities (Table 1). We attempt to broaden the application of PTT in the treatment of cancer metastasis, point out the lacking area and the most promising approaches in this challenging field.

Table 1

Summary of current PTN in treating cancer metastasis by PTT alone or their combinational therapy.

The schematic illustration of PTT of cancer metastasis with various PTN.

(Click on the image to enlarge.)

2. Possible strategies of PTT for treating cancer metastasis

The metastasis of cancer cells is a multistep process, which includes the migration and invasion from primary tumor, intravasation and survival in the circulation system, and extravasation into distant tissues and establishing metastatic foci in the seeded organs [9, 30]. The interruption of any one of these steps can result in the effective suppression of cancer metastasis [1, 30-32]. PTT alone or its combinational therapy can kill the cancer cells in the primary tumor or local metastasis nearby in the early stage of metastasis, inhibit the cell migration and invasion activities, and eradicate the metastatic cancer cells in distant metastatic sites[19, 22, 33]. In view of the unique advantages of PTT, it is highly promising to reduce the metastasis of many types of cancer with the following strategies (Scheme 1):

(1) Direct eradication of cancer cells with PTT alone. Since NIR laser can penetrate soft tissues to a couple of centimeters, PTT can effectively induce the ablation of primary tumor or lymph metastasis in the superficial tissues [24, 34-37]. Upon NIR laser irradiation, PTT can directly kill the cancer cells in the primary tumor sites and lymphatic metastasis via hyperthermia, or even eradicate cancer stem cells and tumor initiating cells, thereby inhibiting their further metastasis in distant organs [38-40]. In addition, the migration and invasion activities of cancer cells can be obviously inhibited at mild hyperthermia without inducing obvious cell death, due to the inhibitory effects of hyperthermia on the expression of a variety of metastasis-related factors including matrix metalloproteinase (MMP-2/9), Twist, vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1), etc [19, 41-43].

(2) Imaging-guided PTT. Multimodal imaging can provide PTT with real-time guidance to treat metastatic disease with greater specificity and sensitivity, enabling better therapeutic planning before and during the operation of PTT [44-46]. The imaging guidance can be used to minimize the side effects by specifically irradiating the tumor or metastatic sites, and optimize the suitable time of irradiation when PTN reaches the peak accumulation to improve the therapeutic efficacy [44].

(3) Efficient combination of PTT with current treatment modalities. Due to the heterogeneous distribution of PTN in tumor, complete eradication of tumor cells with PTT alone is difficult [26, 28]. Moreover, due to the limitation of penetration depth of NIR light in deep tissues, the direct eradication of metastatic cancer cells or metastatic nodules in distant organs with PTT alone remains a great challenge. Accordingly, PTT is efficiently combined with the current management modalities of radiotherapy, chemotherapy and immunotherapy to treat normal cancer cells and metastatic cells in a synergistic manner to achieve the desired efficacy on cancer metastasis.

3. PTT alone with various PTN

PTT can be used to combat the initiation of cancer metastasis in the primary tumor sites or early metastasis in lymph nodes to suppress their further metastasis in distant organs [19, 35, 38]. The NIR laser irradiation can be elaborately adjusted to induce the hyperthermia damage of cancer cells only in the tumor sites or lymph metastasis with minimal invasiveness and high specificity. To date, various PTN of gold nanoparticles, multi-walled carbon nanotube (MWNTs) and NIR dyes based nanoagents have been used for treatment of cancer metastasis [19, 24, 47]. For instance, a polyethylene glycol (PEG) functionalized MWNTs and trifolium-like platinum nanoparticles were developed for effective photothermal ablation of bone metastasis by PTT treatment (Figure 1A) [47, 48]. Considering the deeper tissue penetrating ability of laser in the second NIR window (1000-1400 nm, NIR-II), we recently have developed an ammonium-tungsten-bronze ((NH4)xWO3) nanocube in NIR-II for PTT of metastatic breast cancer[38]. Upon 1064 nm laser, the nanocube could induce significant cell necrosis and apoptosis of metastatic cancer cells, and was evidenced as a promising PTN for effective treatment of primary tumor and lung metastases in a metastatic breast cancer model. Likewise, Kodama et al found that gold nanorods (GNRs) upon NIR-II laser irradiation could effectively suppress the tumor growth in the proper axillary lymph nodes, providing a potential therapeutic method for treating metastasis in lymph nodes [24].

The specific targeting of PTN to the sites of primary tumor or lymph node metastases can be an essential prerequisite for the efficient treatment. To improve the specific distribution of PTN in primary tumor site, we put forward a deep tumor-penetrating NIR probe (DiR) loaded PTN (DPN) for PTT of tumor progression and metastasis of breast cancer (Figure 1B) [19]. The nanometer-sized DPN (20-30 nm) could penetrate into the deep of tumor tissues and be changed into nano-firebombs upon NIR irradiation for photothermal ablation of cancer cells. The cell proliferation and migration activities of metastatic 4T1 breast cancer cells were obviously inhibited by DPN with NIR irradiation. In particular, the tumor growth and lung metastasis of breast cancer were efficiently suppressed by a single PTT treatment. Moreover, to increase the targeting avidity of PTN in lymph metastasis, Liu et al fabricated a PEGylated gold shelled iron oxide nanocluster (IONC@Au-PEG), and provided a magnetic-targeting enhanced strategy to treat the lymph node metastasis (Figure 1C) [35]. Upon an external magnetic field focused on the tumor metastasis region, the accumulation of PTN at the sentinel lymph nodes (SLNs) could be obviously improved. Accordingly, the lung metastasis was effectively inhibited and the animal survival was remarkably prolonged with PTT treatment.

4. Imaging guided PTT

To ensure the safety and efficacy of the photothermal ablation, the image guidance can provide valuable information to improve the therapeutic regimens with PTT [49-53]. To date, multimodal imaging including X-ray computed tomography (CT), photoacoustic (PA) imaging and magnetic resonance imaging (MRI) has been explored for the guidance [46, 54, 55]. The lymphatic metastasis is an important pathway of cancer cells spread, and the SLNs nearby the primary tumor are commonly the host of metastatic cancer cells during the early stage of metastasis [56, 57]. The multimodal imaging guidance can be used to identify the location of lymphatic node metastasis and optimize the therapeutic regimens in full course of PTT treatment. However, current approaches is mainly limited in the lymph node metastasis mapping, and rarely observed in the imaging of distant metastases in deep tissues of lung, liver or brain, etc.

MRI is the most widely used imaging guidance in lymph node mapping during PTT treatment, which is achieved by exploiting the inherent lymph targeting and imaging capability of PTN. The manganese oxides functionalized MWNTs (MWNTs-MnO-PEG) and iron oxides nanoparticles modified graphene oxides (GO-IONP) have been developed as effective theranostic agents for diagnosis and treatment of lymphatic metastasis[46, 58]. Under the guidance of MRI and dark imaging, the regional lymph nodes nearby the primary tumor could be readily mapped, and the metastatic lymph nodes were effectively ablated by NIR irradiation (Figure 2A). Moreover, MRI could be combined with fluorescence imaging for multimodal-imaging guided PTT. Liu et al found that the PEGylated single-walled carbon nanotubes (SWCNT-PEG) could be used for NIR-II fluorescence imaging (1000-1400 nm) under low-power 808 nm laser excitation, and also be utilized for T2-weighted MR imaging due to the anchored catalyst metals in SWCNT [44]. The imaging results confirmed the distribution of SWCNT-PEG from primary tumor to the SLNs after local injection. The image-guided PTT could ablate the primary tumor and metastasized cancer cells in SLNs, leading to the efficient inhibition of distant lung metastasis of breast cancer and remarkably prolonged survival benefits. Likewise, they also designed a NIR dye (IR825) and gadolinium (Gd) complexed albumin-based theranostic agent (HSA-Gd-IR825) with high lymph targeting capability for efficient imaging-guided PTT of cancer metastasis [59].

Meanwhile, the X-ray CT and PA imaging has also been involved in the image-guided PTT of cancer metastasis. Recently, Zhao et al developed a powerful theranostic platform with bismuth sulfide (Bi2S3) nanorods for multimodal imaging-guided PTT of cancer metastasis (Figure 2B) [45]. The Bi2S3 nanorods could be used as a powerful CT contrast agent for angiography and organic imaging, and also as a PA imaging agent for monitoring of their real-time distribution in tumor sites. Upon NIR laser, the Bi2S3 nanorods could effectively ablate the primary tumor and further inhibit their lung metastases. Moreover, to improve the selectivity of PTN to the metastatic cancer cells, the targeting-ligand modification has been utilized in lymphatic metastasis imaging. A theranostic W18O49 nanoparticles modified with human epidermal growth receptor-2 (HER-2) antibody was developed for CT image guided PTT of HER-2 positive breast malignancy [54]. Due to the high X-ray attenuating and PTT potency, the lymph nodes in the mice bearing HER-2 positive metastasis could be clearly distinguished under CT guidance and selectively eliminated by NIR laser ablation, resulting in the extended survival period. Similarly, the metastases in SLNs could be detected by integrated PA imaging with the folate conjugated golden carbon nanotubes and further purged by PTT [55].

5. Efficient combination of PTT with current therapeutic modalities

The combination of different therapeutic strategies has been proven with great potential in cancer therapy in both fundamental and clinical studies. Herein, PTT was efficiently combined with radiotherapy, chemotherapy or immunotherapy to exert the synergistic therapeutic efficacy for cancer metastasis treatment. However, a relative limited number of studies have described the benefits of the combination of PTT with chemotherapy, and few approaches is mentioned in the combination of PTT with radiotherapy or immunotherapy.

5.1 PTT in combination with radiotherapy

The hyperthermia has been evidenced to potentiate radiotherapy, which makes the combination of PTT with radiotherapy a reasonable and attractive approach for treating metastatic cancer [40, 60]. To date, only copper sulfide (CuS) nanoparticles have been employed for this application (Figure 3). Liu et al added 131I into iodine doped CuS nanoparticles to make the CuS/[131I]I nanoparticles, and then functionalized with PEG to form a single nanoagent for combined PTT/radiotherapy of metastatic tumors[60]. The synergistic therapeutic efficacy could be achieved by utilizing the intrinsic higher NIR absorbance and the doped 131I-radioactivity (Figure 3A). The combined PTT/radiotherapy remarkably inhibited the lung metastasis and greatly prolonged the animal survival, providing a potential strategy for combined therapy of metastatic tumors. Likewise, Li et al designed a 64Cu labeled CuS ([64Cu]CuS) nanoparticles for combined PTT/radiotherapy of metastatic breast cancer by depletion of tumor initiating cells (Figure 3B) [40]. The combined radiotherapy/PTT therapy significantly inhibited the tumor growth and prolonged the animal survival. Moreover, the number of metastatic nodules in the lung and the formation of tumor mammospheres in 4T1-induced metastatic breast cancer model were greatly reduced by the combined therapy with [64Cu]CuS nanoparticles.

5.2 PTT in combination with chemotherapy

Chemotherapy is one of the most commonly used modalities in cancer metastasis treatment [2, 3], which can be efficacious in treating both the primary tumor and metastatic lesions in the distant sites. In recent years, the combination of PTT with chemotherapy has attracted the most attention to perform the synergistic effects on cancer metastasis [26, 61, 62]. The gold nanostructure and doxorubicin (DOX) are the mostly utilized combination for the PTT/chemotherapy. Therein, the gold nanoclusters or nanorods were used as photothermal agents for PTT, while DOX was employed as anticancer drug for chemotherapy, enabling their synergistic combination therapy. Recently, we have developed a DOX-loaded DNA wrapped gold nanorods (GNR@DOX) for combination therapy of metastatic breast cancer [20]. Upon NIR irradiation, the progression of primary tumor and lung metastasis of breast cancer were greatly suppressed by the combination therapy with GNR@DOX nanoparticles. Moreover, Qian et al developed a DOX loaded mesoporous magnetic gold nanoclusters for PTT/chemotherapy of metastatic breast cancer [63]. With the assistance of extra-magnetic field, the nanoclusters could be efficiently targeted to the tumor sites of 4T1 breast cancer model. Under the combinational therapy, the pulmonary and mediastinal metastasis were efficiently prevented, leading to a significant prolongation of animal survival. In particular, Chen et al designed a thermo- and pH- sensitive polymer functionalized mesoporous silica coated gold nanorods loading DOX for NIR laser-induced targeted cancer therapy (Figure 4A) [23]. The nanocomposite could simultaneously deliver the heat and anticancer drugs to tumor sites by a single nano-agent in a laser-motivated mechanism with facile control of the area, time and dosage, thereby resulting in an efficient eradiation of tumor growth and lung metastasis. In addition, a SV119-gold nanocage conjugates loading DOX could selectively and effectively eradicate the cancer stem cells of breast cancer by the combinational therapy [64]. Despite these promising approaches of the combination, the possible further clinical translation could be greatly hindered by the safety concerns of the nonbiodegradable gold nanostructure.

To improve the potential in term of clinical translation, Liu et al designed a multifunctional “Abraxane-like” nanodrug (HSA-ICG-PTX) with the US Food and Drug Administration (FDA) -approved agents of albumin (HSA), NIR probe of indocyanine green (ICG) and anticancer drug of paclitaxel, for combination cancer therapy of metastatic breast tumors (Figure 4B) [22]. The HSA-ICG-PTX nanodrug could effectively integrate the photothermal and chemotherapy with NIR imaging in a single nanoagent, which completely eliminated the subcutaneous tumors and displayed evident synergistic therapeutic benefits in treating metastatic breast cancer. The HSA-ICG-PTX nanodrug exhibits great performances in both imaging and combinational therapy, and demonstrated great promise for potential clinical translation.

5.3 PTT in combination with immunotherapy

Immunotherapy has been considered as the ultimate approach for cancer treatment, which can be achieved by exploiting the patient's own immune system to recognize and eliminate cancer cells [65]. PTT can induce tumor cell death upon local NIR laser irradiation, and the dying cancer cells can release the tumor antigens into the surrounding milieu to prime the antitumor immune responses [66]. Most importantly, the combination of PTT with immunoadjuvant could induce an in situ autologous cancer vaccine (inCVAX) (also known as laser immunotherapy)[21]. The FDA-approved NIR probe of ICG was selected as an ideal candidate for PTT, while the semi-synthetic glucosamine polymer of N-dihydro-galacto-chitosan (GC) was optimized as immunoadjuvant with efficient immunological stimulated functions. Upon NIR laser irradiation, the combination of ICG with GC could provide long-term curative effects and anti-tumor immune responses, thereby eradicating the residual primary and metastatic cancer cells. The therapeutic efficacy has been proved in the preclinical studies and clinical metastatic breast cancer and melanoma pilot trials.

Moreover, the combination of PTT with immunotherapy can improve the therapeutic efficacy on both primary tumor and metastatic cancer cells in the distant sites in a complementary manner. Foster et al found gold nanoshell based PTT could promote the expression of proinflammatory cytokines and chemokines, and induce the maturation of dendritic cells (DC) within tumor-draining lymph nodes, leading to the priming of antitumor CD8+ effector T cell responses. The combination of PTT with adoptively transferred tumor-specific T cells efficiently eliminated the tumor growth at distant sites and abrogated the outgrowth of lung metastases [67]. Similarly, Liu et al found the PEGylated SWCNTs could be used for PTT of primary tumor to release the tumor-associated antigens, and simultaneously act as an immunological adjuvant to promote the maturation of DC and production of anti-tumor cytokines (Figure 5) [33]. The SWCNTs based PTT in combination with anti-CTLA-4 antibody therapy effectively suppressed the incidence of the lung metastasis in mice and prolonged the animal survival.

6 Perspectives and Conclusion

Numerous types of PTN have been developed with encouraging therapeutic efficacy for PTT of metastatic cancer in many preclinical animal experiments. Despite their effectiveness, the specificity and selectivity of PTN to normal tumor cells and metastatic cells need to be elaborately considered. Moreover, the possible molecular mechanism of PTN on inhibiting cancer metastasis is rarely mentioned in the current state. In addition, most of these current PTN are constructed with inorganic nanomaterials of noble metals, carbon nanotube or graphene, which significantly hampers their clinical applications due to their potential long-term toxicity. To overcome these limitations, PTN requires more sophisticated design and engineering with precise targeting, powerful imaging and synergistic effects to improve the therapeutic outcome on cancer metastasis.

PTT alone can effectively eliminate the cancer cells in primary tumor or regional lymphatic metastasis in the superficial tissues to reduce their further metastasis in distant organs. However, due to the inhomogeneous heat distribution within these tissues, PTT alone is insufficient for complete eradication of cancer cells to avoid the tumor recurrence and metastasis. As a result, PTN should be designed with specific targeting and deep penetration capability in tumor tissues to improve the therapeutic efficacy.

Meanwhile, the high specificity of PTN to normal tumor cells, metastatic cells or even the cancer stem-like cells cannot be ignored, which is particularly important for the imaging-guided PTT. The imaging guidance of current PTN is commonly limited in the primary tumor or lymph node metastasis mapping, and rarely exploited in the imaging of distant metastatic lesions in deep tissues. PTN should be developed with powerful imaging and high targeting to metastatic cancer to provide significant imaging guidance for PTT alone or further combinational therapy.

Moreover, on account of the limited penetration depth of NIR light, PTT is unable to treat the metastatic cancer cells in deep distant sites, which is the major reason for high mortality of cancer metastasis. The efficient combination of PTT with systemic chemotherapy, immunotherapy or stereotactic radiotherapy can be a reasonable alternative method to treat the metastatic cancer. To exert the combined therapeutic effects, the photothermal agents and combined therapeutic agents should be properly delivered in a synergistic manner, which raises more concerns for the development of co-delivered PTN.

In summary, PTT alone, and their combination with the imaging guidance or current therapies have been evidenced with great promise for treating cancer metastasis. However, these benefits are only now starting to be realized in the animal experimental studies, and few confirmed in clinical trials. Going forward, great efforts are greatly needed in the development of biocompatible PTN with efficient therapeutic performance to improve their further clinical translation. We believe that the PTT or their combinational therapy can provide an essential promising therapeutic modality and bring new hope to the future fight against cancer metastasis.

Acknowledgements

The National Basic Research Program of China (2015CB932103 and 2013CB932503), the National Natural Science Foundation of China (81270047, 81521005) and the K.C. Wong Education Foundation are gratefully acknowledged for their financial support.